EP1977742A1 - Mittel zur prävention/behandlung von harnsteinen - Google Patents

Mittel zur prävention/behandlung von harnsteinen Download PDF

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Publication number
EP1977742A1
EP1977742A1 EP07706289A EP07706289A EP1977742A1 EP 1977742 A1 EP1977742 A1 EP 1977742A1 EP 07706289 A EP07706289 A EP 07706289A EP 07706289 A EP07706289 A EP 07706289A EP 1977742 A1 EP1977742 A1 EP 1977742A1
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EP
European Patent Office
Prior art keywords
urolithiasis
acid
salt
calcium
group
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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Application number
EP07706289A
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English (en)
French (fr)
Inventor
Kazuko Sanai
Yuko Tanaka
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Godo Shusei KK
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Godo Shusei KK
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Publication date
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Publication of EP1977742A1 publication Critical patent/EP1977742A1/de
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/365—Lactones
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
    • A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
    • A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/191—Carboxylic acids, e.g. valproic acid having two or more hydroxy groups, e.g. gluconic acid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/02—Drugs for disorders of the urinary system of urine or of the urinary tract, e.g. urine acidifiers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/04—Drugs for disorders of the urinary system for urolithiasis

Definitions

  • the present invention relates to a prophylactic or therapeutic drug for urolithiasis, and more particularly to a prophylactic or therapeutic drug for urolithiasis involving calcium oxalate calculi.
  • Urolithiasis is a disease characterized by severe pain in the abdomen as a main symptom caused by formation of calculi at any site of the urinary tract ranging from a kidney to the urethra.
  • Japan over one hundred thousand of people are thought to suffer from urolithiasis, and the annual incidence rate thereof increases year by year. The incidence rate is higher in young generation, as the life-style of the young generation including in their diet has been changed. Since formation of urinary calculi tends to recur, prevention of the recurrence is a key issue not only from a medical aspect and but also from an economical aspect (Non-Patent Document 1).
  • Non-Patent Document 1 Non-Patent Document 1
  • Non-Patent Document 2 Clinically, most (80%) of the cases of human urinary calculi are considered calcium oxalate calculi and calcium phosphate calculi.
  • a diet therapy is generally employed. In such a diet therapy, patients are advised to follow, for example, (1) to prevent excessive consumption of food having high oxalic acid content or (2) to take sufficient amount of calcium so as to prevent aggravation of calculi which would otherwise be caused by promoted absorption of oxalic acid under insufficient calcium conditions.
  • diet therapies cannot effectively prevent recurrence of formation of calculi (Non-Patent Documents 1 and 3).
  • Non-Patent Documents 4 to 6 D-gluconic acid is known to dissolve calcium phosphate calculi and magnesium phosphate calculi, but not to dissolve calcium oxalate calculi.
  • An object of the present invention is to provide a prophylactic or therapeutic drug effective for urolithiasis, particularly urolithiasis involving calcium oxalate calculi.
  • the present inventors have investigated a variety of drugs in terms of the effect for treating calcium oxalate urolithiasis by use of model rats to which ethylene glycol(EG) has been continuously administered (i.e., calcium oxalate urolithiasis model rats).
  • ethylene glycol(EG) ethylene glycol
  • the inventors have found that L-aldonic acid, a salt thereof, or a lactone form thereof, particularly L-arabonic acid, exhibits an excellent oxalic acid excretion-promoting effect and an effect of reducing the oxalic acid level and the calcium level in the kidneys, to thereby serve as an effective substance for urolithiasis.
  • the present invention has been accomplished on the basis of this finding.
  • the present invention provides a prophylactic or therapeutic drug and food for urolithiasis containing, as an active ingredient, L-aldonic acid, a salt thereof, or a lactone form thereof.
  • the present invention also provides use of L-aldonic acid, a salt thereof, or a lactone form thereof for producing a prophylactic or therapeutic drug and food for urolithiasis.
  • the present invention also provides a method for prevention or treatment of urolithiasis, characterized by comprising administering to a subject in need thereof L-aldonic acid, a salt thereof, or a lactone form thereof.
  • L-aldonic acid exhibits an excellent effect of preventing and treating urolithiasis and high safety, and allows long-term intake. Therefore, the acid is a particularly useful pharmaceutical or food for preventing recurrence of urolithiasis. In addition, L-aldonic acid hardly gives adverse side effect, since virtually 100% of the acid taken by a subject is excreted to urine.
  • the L-aldonic acid employed in the present invention may be an oxidized product of L-aldose.
  • the L-aldose include L-glyceraldehyde, L-threose, L-erythrose, L-lyxose, L-xylose, L-arabinose, L-ribose, L-talose, L-galactose, L-idose, L-gulose, L-mannose, L-glucose, L-altrose, L-allose, and L-glycero-D-manno-heptose.
  • Oxidized products of L-fucose, L-rhamnose, etc. may also be employed.
  • the thus-produced L-aldonic acids are present with the corresponding lactone forms in an equilibrium state. Among these L-aldonic acids, L-arabonic acid is particularly preferred.
  • Examples of the salt of L-aldonic acid include alkali metal salts such as sodium salts and potassium salts; alkaline earth metal salts such as calcium salts and magnesium salts; and metal salts such as copper salts, iron salts, and zinc salts. Of these, alkali metal salts such as sodium salts and potassium salts are particularly preferred.
  • Acinetobacter baumannii which is a microorganism capable of oxidizing aldose
  • a liquid medium containing L-arabinose is inoculated to a liquid medium containing L-arabinose, followed by culturing under stirring and air passage.
  • L-arabinose contained in the culture decreases, and L-arabonic acid forms.
  • calcium carbonate is added in advance to the culture medium
  • the pH of the culture can be stabilized, and a calcium salt of the formed L-arabonic acid is yielded.
  • the culture is filtered to thereby remove solid contents such as microorganism cells.
  • the filtrate is purified through a known technique such as passage through an ion-exchange resin column, to thereby yield high-purity L-arabonic acid.
  • a known technique such as passage through an ion-exchange resin column
  • an alkali metal salt of L-arabonic acid can be produced through a known technique.
  • L-arabonic acid a salt thereof, or a lactone form thereof is particularly preferred, from the viewpoints of the effect of the urolithiasis treatment and safety.
  • L-aldonic acid As described in the Examples hereinbelow, L-aldonic acid, particularly L-arabonic acid, exhibits an excellent oxalic acid excretion-promoting effect and an effect of reducing the oxalic acid level and the calcium level in the kidneys, which are the effects observed in calcium oxalate urolithiasis model animals. Therefore, L-aldonic acid serves as a useful prophylactic/therapeutic drug and food for urolithiasis, preferably calcium urolithiasis, more preferably urolithiasis involving calcium oxalate calculi, particularly urolithiasis mainly caused by calcium oxalate calculi. In addition, L-arabonic acid has high safety. Although absorbability of L-arabonic acid is low, virtually 100% of the absorbed L-arabonic acid is excreted to urine. Thus, it is considered that an adverse side effect other than the target action in the urinary tract is less exerted.
  • the target urolithiasis prevented or treated by the medicine or food according to the present invention is preferably urolithiasis involving calcium oxalate calculi.
  • urolithiasis according to the present invention both of an upper urolithiasis which produces calculi in the kidney or urinary tract and a lower urolithiasis which produces calculi in the bladder and urethra.
  • the medicine of the present invention may be administered perorally or parenterally.
  • oral administration is preferred.
  • the medicine is preferably provided in the form of a peroral composition.
  • the form of the composition include powder, granules, tablets, capsules, solution, and syrup.
  • a pharmacologically acceptable carrier such as an excipient, a disintegrant, a lubricant, a binder, a moistening agent, a dispersant, a preservative, a sweetening agent, a fragrant material, or a coating agent may be employed.
  • the parenteral administration means include intravenous administration, hypodermal administration, intradermal administration, intramuscular administration, administration via urinary tract, and percutaneous administration. When administered through the urinary tract, the medicine may be topically administered through the urinary tract or in the form of bladder irrigation composition.
  • a possible form of the food according to the present invention is a functional food such as "food for specified health use.”
  • products of the functional food may be labeled with, for example, "for prevention of urolithiasis,” or “those who care about urinary calculi.”
  • Examples of the form of such functional foods include beverage, powder, granules, capsules, sweets, and milk products.
  • the daily dose or amount of the medicine or food of the present invention is preferably 100 mg to 10 g (as L-aldonic acid), more preferably 0.5 g to 5 g, for an adult.
  • arabinate salt refers to an equilmole mixture of sodium L-arabonate and potassium L-arabonate (i.e., sodium L-arabonate (480 mg) and potassium L-arabonate (520 mg) in 1 g of mixture).
  • rats were placed in a metabolic cage, and body weight, chow intake, water intake, amount of urine, pH of urine, urinary calcium level, urinary sodium level, urinary potassium level, and urinary oxalic acid level were measured every two weeks.
  • blood was collected from the heart of each rat under anesthesia with ether, and blood calcium level and blood oxalic acid level were determined.
  • the kidneys (left and right) were removed from each rat, and weight of each kidney, calcium level in the kidney, and oxalic acid level in the kidney were measured.
  • the urine samples were deproteinated with 1N perchloric acid (perchloric acid 1 vol. and urine 4 vol.) before measurement. Calcium concentration was determined by means of Calcium C Test Wako (product of Wako Pure Chemical Industries, Ltd.), and oxalic acid concentration was determined through HPLC. In HPLC, a polymer column ICSep ICE-ION-300 for organic analysis (product of Transgenomic), a mobile phase of 0.0085N sulfuric acid, and an RI detector were employed. Blood samples were deproteinated with 1N perchloric acid (perchloric acid liquid 1 vol. and blood 1 vol.), and calcium concentration and oxalic acid concentration were determined in the same manner.
  • the amount of calcium in a kidney was determined by ashing a portion of the kidney at 550°C for 18 hours, dissolving the ash in 1% HCl, and measuring Ca level by means of Calcium C Test Wako.
  • the oxalic acid level in a kidney is determined by homogenizing a portion of a kidney with 1N perchloric acid and measuring the level through HPLC.
  • the pH of urine samples was determined by means of a single-drop pH meter (product of Shindengen Electric manufacturing Co., Ltd.), and the urinary sodium level and urinary potassium level were determined by means of a compact ion-meter (product of Horiba, Ltd.).
  • the disease group (EG-administered) (hereinafter referred to as urolithiasis group) and the arabonate salt-administered group exhibited a comparatively favorable increase in body weight. No difference was observed in the weight increasing tendency among the three groups including the normal group ( Fig. 1 ). The water intake and urine amount were varied depending on the time point of measurement, but no difference was observed in the variation tendency among the three groups. Therefore, there is no difference in amount of administered EG between the urolithiasis group and the arabonate salt-administered group (Table 9).
  • Fig. 2 is a photograph showing the appearance of kidneys of the rats of the all tested groups.
  • the urolithiasis group six of the six tested rats exhibited hypertrophy and abnormal color of kidneys, with considerably varied degrees.
  • the arabonate salt-administered group five of the six tested rats exhibited improvement of kidney appearance.
  • One rat (No. 1) of the group could not be evaluated.
  • the weight of a kidney and the oxalic acid level in the kidney significantly decreased as compared with the urolithiasis group (p ⁇ 0.05).
  • the calcium level in the kidney was lower as compared with the urolithiasis group, the difference could not be evaluated with significance due to large variation in the data (Table 7).
  • Kidney weight, Ca level in the kidney, and oxalic acid level in the kidney n Weight (g) Ca level ( ⁇ mol) Oxalic acid level ( ⁇ mol) Normal group 6 3.1 ⁇ 0.19 8.2 ⁇ 0.46 110.0 ⁇ 6.60 Urolithiasis group 6 6.6 ⁇ 0.35** 6641.3 ⁇ 1536.36** 6615.9 ⁇ 982.67** Arabonate salt-administered group 6 5.2 ⁇ 0.48 + 3386.9 ⁇ 1088.72 3461.2 ⁇ 977.94 + av. ⁇ standard error, **: P ⁇ 0.01 vs. normal group, +: P ⁇ 0.05 vs. urolithiasis group
  • the LD 50 of L-arabonic acid was found to be about 10 g/kg, indicating that L-arabonic acid is a high-safety substance.
  • the blood L-arabonic acid level five minutes after intravenous administration of sodium L-arabonate was 7.0 ⁇ 0.72 ⁇ mol/mL, which decreased to about the half value 22 minutes after administration.
  • L-Arabonic acid virtually disappeared from blood 2 hours after administration.
  • the blood D-gluconic acid level of the rats in the sodium D-gluconate-administered group was considerably low.
  • Table 12 shows that almost 100% of sodium L-arabonate which had been intravenously administered was excreted to urine within 24 hours from administration.
  • only about 10% of sodium D-gluconate was excreted to urine for 24 hours, and a large portion thereof is thought to be metabolized and consumed in the body.
  • L-arabonic acid is not metabolized in the body and is immediately excreted to urine.

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • Medicinal Chemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Engineering & Computer Science (AREA)
  • General Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Urology & Nephrology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Mycology (AREA)
  • Nutrition Science (AREA)
  • Food Science & Technology (AREA)
  • Polymers & Plastics (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Coloring Foods And Improving Nutritive Qualities (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
EP07706289A 2006-01-31 2007-01-30 Mittel zur prävention/behandlung von harnsteinen Withdrawn EP1977742A1 (de)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
JP2006022482 2006-01-31
PCT/JP2007/000040 WO2007088704A1 (ja) 2006-01-31 2007-01-30 尿路結石症予防治療薬

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US (1) US20100227923A1 (de)
EP (1) EP1977742A1 (de)
JP (1) JPWO2007088704A1 (de)
KR (1) KR20080091774A (de)
CA (1) CA2635800A1 (de)
WO (1) WO2007088704A1 (de)

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5070085A (en) * 1987-04-10 1991-12-03 Oxycal Laboratories, Inc. Compositions and methods for administering therapeutically active compounds
JP2941163B2 (ja) * 1993-02-19 1999-08-25 武田薬品工業株式会社 ペットの尿結石症治療・予防剤および治療方法
JP2005021153A (ja) * 2002-12-26 2005-01-27 Toyo Suisan Kaisha Ltd アクリルアミドを低減化し得る加熱調理食品の製造方法
EP1782805A4 (de) * 2004-08-05 2007-08-08 Godo Shusei Kk Zusammensetzung zur beschleunigung der calciumabsorption

Non-Patent Citations (1)

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See references of WO2007088704A1 *

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CA2635800A1 (en) 2007-08-09
JPWO2007088704A1 (ja) 2009-06-25
WO2007088704A1 (ja) 2007-08-09
US20100227923A1 (en) 2010-09-09
KR20080091774A (ko) 2008-10-14

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